PROJECT SUMMARY Allergic diseases are increasing in prevalence worldwide. Existing allergy increases the risk for developing another allergy in the same individual, with approximately 80% of children with atopic dermatitis developing asthma or allergic rhinitis later in life in a process known as the ?atopic march?. Mast cells are long-lived cells that are important for allergic responses and progression. Innate memory in mast cells is the novel concept that initial activation events shape the cell's functional fate and future responses. Recent studies have defined ?innate memory? in monocytes and NK cells, whereby initial activation alters the phenotype of response to a different second stimulus (i.e. training). In two landmark Science papers, groups show that innate memory is regulated at the epigenetic level and results in an altered metabolism and inflammatory potential of these cells. Mast cells are longer-lived cells, and atopic patients are often 1) poly-sensitized, and 2) experiencing repeated episodes of reactivity. Therefore, I hypothesize that mast cells might similarly undergo phenotypic alterations that reflect a ?memory? of prior activation events, or training. My preliminary data using RNAseq profiling of mast cells undergoing recurrent activation events to different IgE/antigen combinations has defined a transcriptional signature for trained mast cells. Mechanistically, this signature includes genes that regulate type 2 immune responses, cell adhesion, vascular permeability, and survival. I am proposing to focus on the mechanisms (epigenetic, metabolic, etc.) that are responsible for this phenomenon as well as if other known mast cell stimuli are cable of inducing this memory signature. We specifically propose to focus on Interleukin 33 (IL-33), a cytokine that has been extensively linked to allergy and severe respiratory diseases, since it is the most significantly up-regulated genes in trained mast cells. Our lab was the first to publish that IL-33 is expressed by mast cells, but the functional consequences of this remains unclear. I am a MD/PhD student at Northwestern University in the Division of Allergy-Immunology in the second year of graduate school. The environment in which I am training is perfectly suited for me to study both the basic science and clinical aspects of mast cell innate memory in the context of allergic diseases. This proposal aligns with my career goals and the mission of the agency because it seeks to understand the cellular mechanisms driving the atopic march for which there are no effective therapies.